The present studies in rats have further characterized the natural killer (NK) cell system in rats. Results using a wide variety of target cells have shown that the naturally cytotoxic effector cells for both normal bone marrow and tumor targets are all included in the large granular lymphocyte (LGL) subpopulations. Studies with transplantable LGL leukemias in F344 rats have demonstrated close similarity with normal LGL. Similarities were also noted between these LGL tumors and previously reported cases of human T Gamma-CLL. Biochemical analysis of these rats LGL leukemias has resulted in the purification of cytoplasmic granules containing a highly cytoplasmic active protein of approximately 60 kdf. Rabbit antibodies against these granules block both rat and human NI, antibody-dependent cellular cytotoxicity (ADCC), and inhibit the growth of the fungus, Crypotococci neoformans. Molecular biologic studies have also shown the lack of Beta-chain rearrangement or mRNA expression, suggesting that the T cell receptor is not involved in the recognition of target cells by LGL. The present studies demonstrate that a cytoplasmic granule component is necessary for the lytic activity of LGL in both NK and ADCC, and provide the first direct evidence that a secretory event involving these granules is part of the lytic process for both tumor cells and fungi.